Amorphous form of an AKT inhibiting pyrimidinyl-cyclopentane compound, compositions and methods thereof

ABSTRACT

Disclosed is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride, forms, formulations, pharmaceutical compositions, processes of manufacturing and methods of use thereof.

PRIORITY OF INVENTION

This application claims priority to U.S. Provisional Application No.61/648,536 that was filed on 17 May 2012. The entire content of thisprovisional application is hereby incorporated herein by reference.

FIELD OF THE INVENTION

Disclosed herein are forms and formulations of a pyrimidinylcyclopentanecompound with therapeutic activity against diseases such as cancer andprocesses for making the same.

BACKGROUND OF INVENTION

The Protein Kinase B/Akt enzymes are a group of serine/threonine kinasesthat are overexpressed in certain human tumors. International PatentApplication Publication Number WO 2008/006040 and U.S. Pat. No.8,063,050 discuss a number of inhibitors of AKT, including the compound(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one(GDC-0068), which is being investigated in clinical trials for thetreatment of various cancers. The free base and dihydrochloride saltform of GDC-0068 isolated in Example 14 of U.S. Pat. No. 8,063,050 arehygroscopic and difficult to develop into a solid dosage form. What isneeded are forms and formulations of GDC-0068 and its salts that haveimproved pharmaceutical properties.

SUMMARY OF INVENTION

One aspect includes amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (a compound of formula I), pharmaceuticalcompositions, formulations and a process of manufacturing thereof.

Another aspect includes a mesomorphous form of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-propan-1-onemonohydrochloride, pharmaceutical compositions, formulations and aprocess of manufacturing thereof.

Another aspect includes a condis crystalline form of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, pharmaceutical compositions, formulations and aprocess of manufacturing thereof.

Another aspect includes crystalline forms of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, pharmaceutical compositions, formulations and aprocess of manufacturing thereof.

Another aspect includes compositions comprising(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-propan-1-onemonohydrochloride and solvent, pharmaceutical compositions, formulationsand a process of manufacturing thereof. In certain embodiments, thecomposition is a solid composition.

Another aspect includes compositions comprising solvates of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, pharmaceutical compositions, formulations and aprocess of manufacturing thereof.

Another aspect includes a process of producing amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, comprising spray drying a mixture comprising(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride or a solvate thereof and solvent.

Another aspect includes a process of producing amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, comprising contacting a mixture comprising(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride or a solvate thereof with a gas, for example nitrogenand water.

Another aspect includes a tablet for oral delivery comprising amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.

DESCRIPTION OF FIGURES

FIGS. 1A-B show physical characterization of amorphous form of compoundof formula I. FIG. 1A shows an X-ray powder diffractometry (XRPD)pattern of a diffused halo, typical of amorphous material. FIG. 1B showsa polarized microscopy image. No birefringence was observed.

FIG. 2 shows a thermogravimetric analysis (TGA) profile of amorphouscompound of formula I showing weight loss (due to presence of solvent:water and ethanol) up to 150° C.

FIG. 3 shows a differential scanning calorimetry (DSC) profile ofamorphous compound of formula I where glass transition is evident in thesecond heating cycle after solvent removal in the first heating cycle.Glass transition onset temperature for the sample is 114° C.

FIG. 4 shows a FT-Raman spectra of amorphous compound of formula I.

FIG. 5 shows an XRPD pattern of the product of Example 1, which showsboth diffracted peaks and amorphous halo demonstrating by XRPD.

FIG. 6 shows a polarized light microscopy image of the product ofExample 1, where birefringence is observed.

FIG. 7 shows a water sorption analysis of the product of Example 1, withcontinuous water sorption profile at 25° C. from 0-90% RH (deliquescencepoint at ˜75% RH).

FIG. 8 shows a FT-Raman spectra of the product of Example 1, overlaidwith amorphous form of compound of formula I.

FIG. 9 shows a DSC profile of the product of Example 1. The firstendotherm signifies solvent loss (water and ethanol). The second, sharpendotherm overlaps with a “step change” (change in baseline) event. Toresolve these two events, a temperature modulation (±0.5° C. over 80sec) was used, and the endotherm (with an associated enthalpy change of7-11 J/g) was found to overlap with a glass transition temperature(onset˜130° C.).

FIG. 10 shows a modulated DSC profile of the second endotherm of FIG. 9.

FIG. 11 shows various XRPD patterns as a function of temperature.Heating the the product of Example 1 leads to loss in structure(diffracted peaks start to disappear in the 100-160° C. range) and thesolid-state form becomes amorphous.

FIG. 12 shows various XRPD patters as a function of exposure to watervapor (relative humidity or RH) of the product of Example 1. Uponexposure to water vapor at room temperature (different RH/relativehumidity conditions generated by using different salt solutions) for 5-7days, the starting material loses crystallinity as suggested by loss ofdiffracted peak intensity as a function of increasing RH. Upon dryingthe sample exposed to 60% RH for 4 hours under reduced pressure (topmost XRPD pattern), the crystallinity does not reappear.

FIG. 13 shows representative XRPD patterns of the product of Example 1,(bottom) compared to granules of amorphous form of compound of formula I(prepared according to processes described herein) stored under ICHguidelines for 12 weeks. Diffracted peaks from crystalline regions arenot present in the XRPD patterns of the granules of the amorphous formof formula I in the formulations described herein.

FIG. 14 shows DSC profiles of formulations comprising amorphous compoundof formula I prepared as described herein. The profiles show consistentTg of 124-130° C. (onset) over 12 weeks of storage for the formulation.The water content of granules stays between 3.5-4.5% (T₀ watercontent=3.5-4%).

FIG. 15 shows XRPD profiles of two solvates of compound of formula I(glyceryl caprylate top, glyceryl laurate bottom).

FIG. 16 shows variable temperature XRPD patterns of glyceryl caprylate(Capryol 90™ solvate) of compound of formula I.

FIG. 17 shows variable temperature XRPD patterns of glyceryl laurate(Laurylglycol 90™ solvate) of compound of formula I.

FIG. 18 shows a water sorption analysis of glyceryl caprylate ofcompound of formula I at 25° C.

FIG. 19 shows a water sorption analysis of glyceryl laurate solvate ofcompound of formula I at 25° C.

FIG. 20 shows the XRPD profile for a methyl tert-butyl ether (MTBE)solvate of compound of formula I formed by precipitating the solvatefrom MTBE or a mixture of MTBE with a solvent for example, chloroform.

FIG. 21 shows the XRPD profile for a methyl ethyl ketone (MEK) solvateof compound of formula I formed by precipitating the solvate from MEK ora mixture of MEK with a solvent.

FIG. 22 shows the XRPD profile for a methyl isobutyl ketone (MIBK)solvate of compound of formula I formed by precipitating the solvatefrom MIBK or a mixture of MIBK with a solvent.

FIG. 23 shows the XRPD profile for a toluene solvate of compound offormula I formed by precipitating the solvate from toluene with asolvent.

FIG. 24 shows the XRPD of pre and post milled batches of a compound ofFormula I prepared by Direct Wet Granulation of a composition comprisingpartially crystalline compound of Formula I. Conversion of the partiallycrystalline form to amorphous form at 33% drug load, as well as at 43%drug load, occurs, without solution mediated precipitation.

FIG. 25 shows the moisture sorption isotherm for a postmilled batch of acompound of Formula I prepared by Direct Wet Granulation of acomposition comprising partially crystalline compound of Formula I at43% drug load, which shows that the hygroscopicity of the compound isminimized by use of amorphous/fumed silica as an internal desiccant andthe moisture sorption behavior is comparable to granules prepared fromsolution mediated precipitation of a compound of formula I.

FIG. 26 shows the DVS program for the product of Example 10.

FIG. 27 shows the XRPD profile for the product of Example 10.

FIG. 28 shows the DSC profile for the product of Example 10.

FIG. 29 shows the single crystal lattice structure for the product ofExample 11.

FIGS. 30A-B show the XRPD profiles for the products of Example 11.

FIGS. 31A-C show the XRPD profiles for the products of Example 12(amorphous spray dried compound of formula I).

FIG. 32 shows the XRPD profile of ethyl acetate solvate of compound offormula I.

FIG. 33 shows the XRPD profiles of the ethyl acetate solvate of compoundof formula I under varying drying conditions. Profile 1 shows thesolvate analyzed in a “semi'sealed” sample holder; profile 2 shows thesolvate analyzed in holder open to air; profile 3 shows the solvateanalyzed after heating to 75° C. in a vacuum oven for 1 hour; andprofile 4 shows the solvate heated at 75° C. in a vacuum oven for 5hours.

FIG. 34A shows the single crystal structure for the ethyl acetatesolvate of a compound of formula I, and FIG. 34B shows the calculatedX-ray diffraction profile of the single crystal.

FIG. 35 shows the XRPD profile of ethylbenzene solvate of compound offormula I.

FIG. 36 shows the XRPD profile of ortho-xylene solvate of compound offormula I.

FIG. 37 shows the XRPD profile of meta-xylene solvate of compound offormula I.

FIG. 38 shows the XRPD profile of para-xylene solvate of compound offormula I.

FIG. 39 shows the XRPD profile of cumene solvate of compound of formulaI.

FIG. 40 shows the XRPD profile of tetralin solvate of compound offormula I.

FIG. 41 shows the XRPD profile of MEK solvate of compound of formula I.

FIG. 42 shows the XRPD profile of MIBK solvate of compound of formula I.

FIG. 43 shows the XRPD profile of MBK solvate of compound of formula I.

FIG. 44 shows the XRPD profile of diisobutylketone solvate of compoundof formula I.

FIG. 45 shows the XRPD profile of methyl acetate solvate of compound offormula I.

FIG. 46 shows the XRPD profile of propyl acetate solvate of compound offormula I.

FIG. 47 shows the XRPD profile of isopropyl acetate solvate of compoundof formula I.

FIG. 48 shows the XRPD profile of isobutyl acetate solvate of compoundof formula I.

FIG. 49 shows the XRPD profile of t-butyl acetate solvate of compound offormula I.

FIG. 50 shows the XRPD profile of ethyl ether solvate of compound offormula I.

FIG. 51 shows the XRPD profile of amyl acetate solvate of compound offormula I.

FIG. 52 shows the XRPD profile of glycerol triacetate solvate ofcompound of formula I.

FIG. 53 shows the XRPD profile of ethyl ether ethanol hydrate solvate ofcompound of formula I.

FIG. 54 shows the XRPD profile of t-butyl methyl ether solvate ofcompound of formula I.

FIG. 55 shows the XRPD profile of dimethoxy ethane solvate of compoundof formula I.

FIG. 56 shows the XRPD profile of diethoxy ethane solvate of compound offormula I.

FIG. 57 shows the XRPD profile of dimethoxy propane solvate of compoundof formula I.

FIG. 58 shows the XRPD profile of 2-methyl tetrahydrofuran solvate ofcompound of formula I.

DETAILED DESCRIPTION OF INVENTION

The term “a” as used herein means one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse and in one embodiment plus or minus 20% of the given value. Forexample, description referring to “about X” includes description of “X”.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counter ion.The counter ion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

Compounds of the present invention, unless otherwise indicated, includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds of the present invention, whereinone or more hydrogen atoms are replaced by deuterium or tritium, or oneor more carbon atoms are replaced by a ¹³C or ¹⁴C carbon atom, or one ormore nitrogen atoms are replaced by a ¹⁵N nitrogen atom, or one or moresulfur atoms are replaced by a ³³S, ³⁴S or ³⁶S sulfur atom, or one ormore oxygen atoms are replaced by a ¹⁷O or ¹⁸O oxygen atom are withinthe scope of this invention.

It has been unexpectedly discovered that isolating(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (a compound of formula I) from particular solventsproduces different physical forms of the compound, and that thedifferent forms have different pharmaceutical properties. It has beenfound that certain forms have improved properties useful for formulatingthe compound into stable drug forms for treating diseases such ascancer.

One aspect includes a solid composition comprising a compound of formulaI and solvent. Another aspect includes a crystalline solid compositioncomprising a compound of formula I and solvent. Example solvents for thesolid composition include capryol glycol, lauryl glycol, MEK, MIBK,MTBK, chloroform, dichloromethane, ethyl acetate, toluene,chlorobenzene, ethylbenzene, THF, 2-MethylTHF, 1,2-dichloroethane,ortho-xylene, meta-xylene, para-xylene, anisole, methyl acetate, cumene,tetralin, propyl acetate, isopropyl acetate, diisobutyl ketone, isobutylacetate, t-butyl acetate, amyl acetate, glycerol triacetate,1,2-dimethoxyethane, 1,2-diethoxyethane, 2,2-dimethoxypropane, ethylether, t-butyl methyl ether, water and mixtures thereof (includingether-ethanol mixture). In certain embodiments, the solid compositioncomprises variable levels of solvent. In certain embodiments, the solidcomposition comprises solvent solvated to the compound of formula I.Example solvates of the solid composition include channel or layeredsolvates. In one example, the solid composition comprises compound offormula I, fully substituted with solvent, such as 1:1 molar ratiosolvate. In another example, the solid composition comprises compound offormula I, partially substituted with solvent, such as in a w/w %(solvent:compound of formula I) in the range of about 0.1% to about 20%,alternatively about 1% to about 15%. In one specific example, a solidcomposition comprises a compound of formula I and ethyl acetate in aratio of about 16% to about 1% ethyl acetate.

Another aspect includes a mesomorphous form of compound of formula Icomprising intermediate order, which results from crystallizing thecompound of formula I from a solvent mixture comprising antisolvent.

Another aspect includes a condis crystalline form of compound of formulaI that has intermediate order, resulting from crystallizing from asolvent mixture comprising antisolvent.

Another aspect includes an amorphous form of compound of formula I thatresults from isolating from solvent. The amorphous form has certainimproved pharmaceutical properties and can be formulated into stabledrug forms for treating diseases such as cancer.

Therefore, one aspect includes amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (a compound of formula I).

Another aspect includes a liquid-fill capsule formulation of compound offormula I, comprising a compound of formula I and a liquid fill solvent.Liquid fill solvents for use in the liquid fill formulations includesolvents that comprise a lipidic (for example, C₃₋₂₀ alkyl) group andhydroxyl group. In one example, liquid fill solvents are mono-esters,di-esters and tri-esters of fatty acids (C₃₋₂₀ alkyl or C₈₋₁₈ alkyl) andglycerol, ethylene glycol, propylene glycol or polyethylene glycol.Examples include lipids, such as glyceryl stearates, for example estersof natural fatty, stearic and palmitic acids with glycerin, andalkylglycol caprylates, and the like. Other examples include propyleneglycol monocaprylate type II (Capryol 90™), PEG-32 glyceryllaurate-(Gelucire® 44/14), Propylene glycol monocaprylate type I(Imwitor 792), PEG-6 glyceryl oleate, (Labrafil® M 1944CS), PEG-6glyceryl linoleate, (Labrafil® M 2125 CS), Propylene glycol monolauratetype II, (Lauroglycol 90), Poloxamer 188, (Lutrol F68NF), Poloxamer 407,(Lutrol F127 NF), Polyethyleneglycol (PEG) 1500, Propylene glycol,Glycerol (Glycerin), d-alpha tocopheryl PEG-1000 succinate,(VitaminE-TPGS), PEG-8 caprylic/capric glycerides (Labrasol®), andesters of caprylic or capric fatty acids with glycerin or propyleneglycol (for example, Miglyol 810N or Miglyol 812N).

In another example, liquid fill solvents are those solvents withcritical micelle concentration (cmc) values greater than about 0.9 g/gwith the compound of formula I. In certain embodiments, the liquid fillsolvent is propylene glycol caprylate (in one example, the product soldcommercially as Capryol 90™, Gattefosse). The liquid fill solvent can bepresent in a range of about 36.5% w/w to about 60% w/w depending on thedosage strength, i.e., the amount of compound of formula I. In anotherexample, the liquid fill solvent is a solvent in which the compound offormula I can be dissolved in concentrations between about 0.7 and 1g/g, including propylene glycol monocaprylates (e.g., types I and II),PEG-8 caprylic/capric glycerides, glycyl laurate (for exampleLauroglycol™), glycerol, propylene glycol and PEG-8 caprylic/capricglycerides.

In certain embodiments, the liquid fill solvent is selected from liquidfill solvents described herein that are further compatible withhydroxypropylmethyl cellulose and hard gelatin capsules such aspropylene glycol monocaprylate type II (Capryol 90™) and Lauroglycol™90.

In certain embodiments, the liquid-fill formulation further comprises anantioxidant. Antioxidants include ascorbic acid, methionine, butylatedhydroxyanisole (BHA) and butylated hydroxytoluene (BHT). In one example,the antioxidant comprises BHA. In one example, the antioxidant comprisesBHT. In certain embodiments, the liquid fill formulation comprises about0.1% w/w antioxidant.

In certain embodiments, the liquid-fill formulation further comprisesanti-crystallization additives. In one example, the additive is PVPpolymer.

The liquid-fill formulation allows for unexpectedly high concentrationsof compound of formula I, which allows for the production of a single,high dosage unit with strengths between 100-mg and 400-mg. Such highdoses are generally unachievable with active pharmaceutical ingredientsin the lipid like liquid fill solvent systems. For example, it wasunexpectedly discovered that compound of formula I is surface active inthe presence of propylene glycol caprylate which provides the ability toreach high concentration liquid fill formulations. The critical micelleconcentration for GDC-0068 in propylene glycol caprylate (e.g., Capryol90™) was determined to be 0.945 g/g.

Additionally, several compounds with known high aqueous solubility aswell as poor aqueous solubility were tested for the maximum amounts thatcould be dissolved in Capryol 90™. Highly water-soluble compounds testedwere ascorbic acid, metformin, acetyl salicylic acid andacetaminophenol. Poorly water-soluble compounds tested weregriseofulvin, indomethacin and naproxen. None of the model compoundscould be dissolved at greater than 10% w/w concentration in Capryol 90™.

Therefore, another aspect includes a liquid fill formulation of acompound of formula I, comprising about 100 mg to about 400 mg ofcompound of formula I (measured as free base), about 36.5% w/w to about60% w/w propylene glycol caprylate and about 0.1% w/w antioxidant. Inone example, the antioxidant is BHA. In one example, a liquid-fillformulation comprises 100 mg compound of formula I. In one example, aliquid-fill formulation comprises 400 mg compound of formula I. In oneexample, the formulation further comprises a capsule.

Another aspect includes a tablet formulation, comprising amorphouscompound of formula I and filler. In one example, the formulationcomprises amorphous compound of formula I and silica. In anotherexample, the formulation further comprises inhibitors ofcrystallization, such as PVP or hydroxypropyl methylcellulose (HPMC),and optionally further comprises antioxidant. such as BHT or BHA.

In certain embodiments, the tablet comprises about 33% w/w amorphouscompound of formula I, about 15% w/w silica (in one example, the productsold commercially as Cab-o-sil, Cabot, Corp.), about 43% w/wmicrocrystalline cellulose, about 5% w/w croscarmellose sodium, about2.5% w/w PVP, about 0.1% w/w BHA, and about 1% w/w stearic acid.

Another aspect includes a process of producing amorphous compound offormula I, comprising contacting a compound of formula I with a solvent,and removing the solvent to form the amorphous compound of formula I.

Alternatively, the process of producing amorphous compound of formula Icomprises removing solvent from a solvate of a compound of formula I,such as by drying or contacting the solvate with moist nitrogen or otherinert gas.

Alternatively, the process of producing amorphous compound of formula Icomprises spray drying a solution of compound of formula I to formamorphous material. In one example of spray drying, the material (forexample crystalline or mesomorphous material) is dissovled in a solventand spray dried to produce the amorphous compound of formula I. Examplesolvents for use in the spray drying process include water and ethanol.The starting material can be any form of the compound of formula I, forexample, a solvate of a compound of formula I, such as the ethyl acetatesolvate, or material prepared according to Example 1. In one example,the spray dried amorphous product comprises about 0.01 to about 2.5%residual solvent. In one example, the spray dried amorphous productcomprises about 0.01 to about 1.0% residual solvent. In one example, theethyl acetate solvate is contacted with water and spray dried to giveamorphous compound of formula I comprising less than about 1.0% w/wwater and about 0.25% w/w or less ethyl acetate. In another example, theethyl acetate solvate is contacted with ethanol and spray dried to giveamorphous compound of formula I comprising less than about 1.0% w/wwater, about 2.5% w/w or less ethanol and about 0.25% w/w or less ethylacetate. In certain embodiments, the process further comprises dryingthe spray-dried amorphous material to further reduce the amount of waterand solvent. In one example, the further dried amorphous spray-driedcompound of formula I comprises less than about 0.5% solvent.

In certain embodiments, the contacting of a compound of formula I with asolvent further comprises dissolving the compound of formula I in thesolvent. In certain embodiments, the solvent comprises ethanol. In oneexample, the solvent comprises water. In certain embodiments the solventcomprises ethanol:water, for example in 1:1 mixture. In certainembodiments, the solvent further comprises additives, for example,inhibitors of crystallization, such as polymers, for examplepolyvinylpyrrolidone (PVP), and other additives, such as antioxidants orpreservatives, for example, BHA or BHT.

Another aspect includes a pharmaceutical formulation comprising anamorphous compound of formula I.

Another aspect includes a process of producing a tablet formulationcomprising amorphous compound of formula I, comprising contacting acompound of formula I with a solvent comprising ethanol to form amixture; contacting the mixture with filler comprising crystallinecellulose; and removing the solvent to form the pharmaceuticalformulation comprising amorphous compound of formula I. In certainembodiments, the solvent further comprises water. In certainembodiments, the solvent further comprises stabilizer, for example, PVPpolymer, and antioxidant, for example BHA or BHT.

Another aspect includes a process of producing a tablet formulationcomprising contacting a mesomorphous form of a compound of formula I,cellulose and silica (for example amorphous or colloidal silica). Theprocess includes contacting the mesomorphous form, cellulose and silicawith a solvent mixture of ethanol and water and removing the solventmixture by drying the mixture to form the amorphous form of the compoundof formula I, which is entrapped in the mixture. It was unexpectedlyfound that such a direct wet granulation process would result in anamorphous form of the drug substance of formula I. The hygroscopicity ofthe final formulation obtained by such a direct wet granulation issurprisingly similar to that of the formulation prepared from a solutionmediated precipitation of the compound of formula I alone.

In certain embodiments, the tablet manufacturing process includes (a)dissolving antioxidant and stabilizer in a 50:50 mixture of solventcomprising ethanol, and optionally further comprising water to form amixture; (b) dissolving compound of formula I into the mixture to form asolution; (c) granulating the solution with filler to form granules; (d)drying the granules; and (e) compressing the granules to produce thetablet. In one example, the process further comprises before (e): mixingadditional ingredients to form a blend.

In certain embodiments, the granulating process further compriseshigh-shear granulating the solution with filler comprising crystallinecellulose. In certain embodiments, the filler comprises microcrystallinecellulose. In certain embodiments, the filler further comprises fumedamorphous silica, and optionally further comprises croscarmellosesodium. In one example, the filler comprises highly porousmicrocrystalline cellulose and fumed silica.

In certain embodiments, drying the granules further comprises drying atan elevated temperature. In certain embodiments, the temperature fordrying granules is in the range of about 50° C. and 60° C.

Predicting and controlling the amount of crystallinity in a drug dosageform is important for several reasons including obtaining predictablebioavailability and quality control in manufacturing. It is alsoimportant to have stable drug forms of hygroscopic drug substances toprevent the drug forms from changing crystalline nature. Mesomorphousforms of a compound of formula I, for example, a condis-crystal form ofthe compound of formula I, can have analytically variable levels ofcrystallinity and is hygroscopic. The tablet production processdescribed herein can transform a sample of compound of formula I from amesomorphous form, and in one embodiment a condis-crystal form, to adrug product comprising amorphous compound of formula I, and mitigateshygroscopicity problems (i.e., deliquescence) by adsorbing the compoundof formula I into a highly porous structure of filler (for example,fumed silica) and thereby protecting the compound of formula I from themoisture gain.

Another aspect provides a solid unit oral pharmaceutical dosage formcomprising amorphous compound of formula I in an amount of 100 mg to 400mg calculated as the freebase form, and pharmaceutically acceptablecarrier, diluent, stabilizer or excipient. In certain embodiments, thesolid unit oral pharmaceutical dosage form comprises amorphous compoundof formula I in an amount of 100 mg. In certain embodiments, the solidunit oral pharmaceutical dosage form comprises amorphous compound offormula I in an amount of 400 mg. In certain embodiments, the oraldosage form is a tablet.

Another aspect includes a mesmorphous form of the compound of formula I.Another aspect includes a condis-crystal form of the compound of formulaI.

Another aspect includes a process of producing mesomorphous form ofcompound of formula I, comprising contacting a compound of formula Iwith a solvent comprising antisolvent, for example, ethyl acetate, andremoving the solvent to form the mesomorphous compound of formula I. Inone example, the mesomorphous form is a condis-crystalline form. Incertain embodiments, the solvent further comprises an alcohol, forexample isopropanol. In certain embodiments the solvent comprises ethylacetate:isopropanol in 1:1 mixture.

Antisolvents for the compound of formula I include liquids in which thecompound of formula I has solubility less than about 20 mg/mL. In oneexample, antisolvents include pentane, hexane, cyclohexane, heptane,ethyl acetate, iso-propyl acetate, methyl t-butyl ether (MTBE) andmethyl iso-butyl ketone.

Solvents for the compound of formula I include liquids in which thecompound of formula I has solubility greater than about 20 mg/mL. In oneexample, solvents include water, alcohols such as methanol, ethanol,isopropanol, 2-butanol, t-butanol and 2-methoxy ethanol, polar etherssuch as tetrahydrofuran and 2-methyltetrahydrofuran, toluene,chloroform, dichloromethane, 1,2-dichloroethane and acetone.

Another aspect includes a pharmaceutical formulation comprising a solidcomposition comprising compound of formula I and solvent. Another aspectincludes a pharmaceutical formulation comprising mesomorphous form ofcompound of formula I. Another aspect includes a pharmaceuticalformulation comprising condis-crystal form of compound of formula I.

Another aspect includes a process of producing a pharmaceuticalformulation comprising mesomorphous compound of formula I, comprisingcontacting a compound of formula I with a solvent comprisingantisolvent, for example, ethyl acetate to form mesomorphous compound offormula I.

Another aspect includes a process of producing a pharmaceuticalformulation comprising condis-crystalline compound of formula I,comprising contacting a compound of formula I with a solvent comprisingantisolvent, for example, ethyl acetate to form condis-crystallinecompound of formula I.

Another aspect includes crystalline solvate of compound of formula I,wherein the compound of formula I forms a crystalline solvate withsolvent selected from glyceryl caprylate, glycol laurate, methyl ethylketone (MEK), methyl iso-butyl ketone (MIBK), methyl tert-butyl ketone(MTBK), chloroform, dichloromethane, ethyl acetate, toluene,tetrahydrofuran (THF), 2-Methyltetrahydrofuran (2-MeTHF),1,2-dichloroethane, meta-xylene, anisole, methyl acetate, cumene,isopropyl acetate, diisobutyl ketone, isobutyl acetate, amyl acetate,and mixtures thereof (including ether-ethanol mixture). In certainembodiments, the solvate further comprises water. In certainembodiments, the water forms a hydrate with the compound of formula I orwith the solvated compound of formula I, for example chloroform solvatehydrate and ethanol-ether hydrate.

Another aspect includes crystalline solvate of compound of formula I,wherein the compound of formula I forms a crystalline solvate withsolvent selected from capryol glycol, lauryl glycol, MEK, MIBK, MTBK,chloroform, dichloromethane, ethyl acetate, toluene, chlorobenzene,ethylbenzene, THF, 2-MethylTHF, 1,2-dichloroethane, ortho-xylene,meta-xylene, para-xylene, anisole, methyl acetate, cumene, tetralin,propyl acetate, isopropyl acetate, diisobutyl ketone, isobutyl acetate,t-butyl acetate, amyl acetate, glycerol triacetate, 1,2-dimethoxyethane,1,2-diethoxyethane, 2,2-dimethoxypropane, ethyl ether, t-butyl methylether and mixtures thereof (including ether-ethanol mixture). In certainembodiments, the solvate further comprises water. In certainembodiments, the water forms a hydrate with the compound of formula I orwith the solvated compound of formula I, for example chloroform solvatehydrate and ethanol-ether hydrate.

Another aspect includes solid compositions comprising a compound offormula I and solvent selected from capryol glycol, lauryl glycol, MEK,MIBK, MTBK, chloroform, dichloromethane, ethyl acetate, toluene, THF,2-MethylTHF, 1,2-dichloroethane, meta-xylene, anisole, methyl acetate,cumene, isopropyl acetate, diisobutyl ketone, isobutyl acetate, amylacetate and mixtures thereof (including ether-ethanol mixture). Incertain embodiments, the compositions comprising the solvate furthercomprise water. In certain embodiments, the water forms a hydrate withthe compound of formula I or with the solvated compound of formula I. Incertain embodiments, the solvent is solvated with compound of formula I.

Another aspect includes compositions comprising a compound of formula Iand solvent selected from capryol glycol, lauryl glycol, MEK, MIBK,MTBK, chloroform, dichloromethane, ethyl acetate, toluene, THF,2-MethylTHF, 1,2-dichloroethane, meta-xylene, anisole, methyl acetate,cumene, isopropyl acetate, diisobutyl ketone, isobutyl acetate, amylacetate, chlorobenzene, ethylbenzene, ortho-xylene, THF, 2-MethylTHF,1,2-dichloroethane, ortho-xylene, meta-xylene, para-xylene, tetralin,propyl acetate, t-butyl acetate, glycerol triacetate,1,2-dimethoxyethane, 1,2-diethoxyethane, 2,2-dimethoxypropane, ethylether, t-butyl methyl ether and mixtures thereof (includingether-ethanol mixture). In certain embodiments, the compositionscomprising the solvate further comprise water. In certain embodiments,the water forms a hydrate with the compound of formula I or with thesolvated compound of formula I. In certain embodiments, the solvent issolvated with compound of formula I.

In certain embodiments, the compound of formula I forms a crystallinesolvate with solvent selected from Capryol glycol and lauryl glycol.

EXAMPLE 1

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride

To a 500 mL reactor was added tert-butyl((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate(49 g) and IPA (196 mL) and the reactor was heated to 50° C. A solutionof HCl in 2-propanol (3M, 90 mL) was added to maintain the temperaturefrom 50-70° C. The solution was maintained at 60° C. for 19 hours andthe mixture was cooled to 0-5° C. Amberlyst A-21 resin (60.5 g) waswashed with water (50 mL) and purged with N2 for 5 min to remove excesswater. The resin was then washed with 2-propanol (50 mL) and purged withN2 for 5 min to remove excess 2-propanol. The reaction mixture wasre-circulated through the packed resin bed for at least 2 hours until pH3.55-7.0 was reached. The resin bed was purged with N2 for 5 min,collecting all the filtrates. The resin was washed with 2-propanol (294mL), and the resin was purged with nitrogen for 5 min, combining all thefiltrates. To the combined solution was added decolorizing charcoal (20g) and the mixture was stirred at 15-25° C. for 1-2 hours. The charcoalwas then filtered through diatomaceous earth and the solution wasdistilled under vacuum at 25-35° C. Ethyl Acetate (333.0 mL) was chargedto obtain a ˜87.5:12.5 EtOAc:IPA ratio. A seed slurry (1 g) of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride in EtOAc:IPA (˜6 mL, 87.5:12.5) was added to thereactor and the mixture was stirred at 20-25° C. for 1 hour. The slurrywas constant volume solvent-switched to EtOAc at 20-30° C. until a ratioof EtOAc:IPA≧97:3 was reached. The reactor was cooled to 0-10° C. andthe slurry was filtered. The filter cake was washed with EtOAc (115 mL).Dried under vacuum at 85° C. for 16 hours to afford(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride as an off-white solid: 41.9 g (94% yield).

Table 1 below and FIG. 5 show the characteristic XRPD peaks and patternfor the isolated(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.

Therefore another aspect includes a form of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride having X-ray diffraction pattern that includescharacteristic peaks, in 2-Theta (+/−0.2), occurring at 7.1. In anembodiment, the form also includes one or more characteristic peaks at8.4, 8.8, 10.5, 12.7, 13.7, 13.9, 17.4, 21.1 and 22.3.

TABLE 1 2-Theta d(Å) BG Height H% Area A% FWHM 7.113 12.4168 30 104100.0 1093 103 0 0.150 8.387 10.5334 29 24 23.5 389 35.6 0.227 8.83510.0007 29 23 22.6 331 30.3 0.201 10.492 8.4248 25 28 27.0 212 19.40.108 12.693 6.9682 28 13 12.4 72 6.6 0.080 13.679 6.4684 31 26 25.3 32229.4 0.174 13.875 6.3772 31 14 13.8 392 35.8 0.390 17.435 5.0824 37 2120.1 279 25.5 0.190 21.095 4.2081 35 23 21.9 248 22.7 0.155 22.2793.9870 35 15 14.9 144 13.2 0.133

EXAMPLE 2 Liquid Fill Capsule

Liquid fill formulations containing 47.5% w/w(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride were prepared in both capryol 90 and lauroglycol 90 toyield capsule dosage strength of 300 mg.

Capryol 90

Using a jacketed beaker, Capryol 90 (55.06 g) was heated toapproximately 60° C., while mixing with a top down mixer at 300 RPM. BHA(149.9 mg) was added to the Capryol 90.(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (49.96 g) was slowly added to the solution over thecourse of approximately 10 minutes. The impeller speed was increased to1000 RPM and the solution mixed for approximately 80 minutes until allsolids were dissolved. The solution was then sonicated for approximately5 minutes to degas, and then allowed to cool to room temperature priorto capsule filling. The compounded liquid (700 mg) was filled into size0 white gelatin capsules using a positive displacement pipette. Allcapsules were held upright in filling trays until banding. Using agelatin banding solution of about 22% gelatin and 1% polysorbate 80 inwater (% wt/wt), all capsules were banded using an automated capsulebander (Schaefer Technologies Laboratory Scale Bander). Sufficientsolution was made to produce 150 capsules. After compounding and fillingcapsules, there were a total of 140 capsules produced. No capsules wererejected after filling, or banding. The total yield was 93%.

Lauroglycol 90

Using a jacketed beaker, Lauroglycol 90 (55.07 g) was heated toapproximately 60° C., while mixing with a top down mixer at 400 RPM. BHA(150.2 g) was added to the Lauroglycol 90.(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (49.97 g) was slowly added to the solution over thecourse of approximately 10 minutes. The impeller speed was increased to1000 RPM and the solution mixed for approximately 100 minutes until allsolids were dissolved. The solution was then sonicated for approximately20 minutes to degas, and then allowed to cool to room temperature priorto capsule filling. The compounded liquid (700 mg) was filled into size0 white HPMC capsules using a positive displacement pipette. Allcapsules were held upright in filling trays until banding. Using agelatin banding solution of about 22% gelatin and 1% polysorbate 80 inwater (% wt/wt), all capsules were banded using an automated capsulebander (Schaefer Technologies Laboratory Scale Bander). Sufficientsolution was made to produce 150 capsules. After compounding and fillingcapsules, there were a total of 135 capsules produced, for a yield of90%. While banding, 5 capsules were rejected. After the banding cooledovernight, and the capsules were inspected, an additional 7 capsuleswere rejected. A total of 123 acceptable capsules were obtained for ayield of 82%.

EXAMPLE 3

Tablet Formulation Containing a Dense Grade of Silica Amount AmountAmount (mg)/ (mg)/ (gm)/ 300-mg 100-mg 50 gm Ingredient tablet tabletbatch (S)-2-(4-chlorophenyl)-1-(4- 330 110 16.5((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one monohydrochloridePolyvinyl pyrolidone (PVP K30) 25 8.33 1.25 Butylated hydroxyl anisole 10.33 0.05 Croscarmellose sodium (internal 30 10 1.5 phase)Croscarmellose sodium (external 20 6.67 1.0 phase) Syloid 244 140 46.677.0 Microcrystalline cellulose (PH 101) 444 148 22.2 *Ethanol/Water q.s.q.s. q.s. Stearic acid 10 3.33 0.5 *Ethanol/water is evaporated duringdrying

(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I) was screened through a #30screen to de-lump the large particles. BHA and PVP were dissolved intothe ethanol-water solution (50:50 mix to make a total of 15 mL). Thecompound of formula I was slowly added to the solution with vigorousstirring conditions. Small amounts were added in incremental portions soas to allow complete dissolution. In a 0.5 L Diosna granulator bowl, thebatch amounts of microcrystalline cellulose, Syloid 244 andcroscarmellose sodium were mixed for 2 minutes in the high sheargranulator using the impeller under a dry state so as to get a uniformmixture. This was followed by drop-wise addition of the solutioncontaining the compound of formula I under constant agitation of thepowder bed in the high shear granulator. After adding all the solution,the beaker was rinsed with about 2 mL of water and added dropwise intothe granulation under agitation to so as to ensure the entire batchamount of solution is incorporated into the granulation. This wasfollowed by a final rinse step of about 1 mL ethanol also added withagitation. After completion of the rinse addition, the impeller speedwas increased and the chopper blade was turned on so as to perform thekneading or wet massing and facilitate particle growth. After about 2minutes of kneading, a clear visual increase in particle size wasobservable and the granulation end-point could be confirmed by granulesqueeze test. The granules were dried in a tray oven for about 4.5 hoursto remove the ethanol and water. The final loss on drying from thegranules was measured to be less than 3% w/w suggesting a drygranulation. Using the dried granules and re-calculating the exactamount of croscarmellose sodium and stearic acid required for the batch,pre-screened stearic acid was added stepwise to the batch and mixed on aturbula mixer. The final lubricated granulation was compressed on aCarver hydraulic press using capsule shaped tooling in order to compress300-mg potency tablets at a press weight of 1000-mg.

EXAMPLE 4

Scale-up Process for Tablet Manufacture Amount Amount Amount (mg)/ (mg)/(gm)/ 300-mg 100-mg 1000 gm Ingredient tablet tablet batch(S)-2-(4-chlorophenyl)-1-(4- 330 110 330 45R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride Polyvinyl pyrolidone (PVPK30) 25 8.33 25 Butylated hydroxyl anisole 1 0.33 1 Croscarmellosesodium (internal 30 10 30 phase) Croscarmellose sodium (external 20 6.6720 phase) Fumed silica (Cabosil MP-5) 140 46.67 140 Microcrystallinecellulose (PH 101) 444 148 444 *Ethanol/Water q.s. q.s. q.s. Stearicacid 10 3.33 10 *Ethanol/water is evaporated during drying

The formulation shown above was processed in a Diosna 4 L granulatorbowl. PVP-K-30 (25 g) and BHA (1 g) were dissolved into a mixture of 75ethanol (200 proof) and 75 mL water.(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I) was screened through a #30mesh screen and slowly added to the vessel containing the BHA and PVPsolution in ethanol-water. The compound of formula I was dissolved underhigh speed stirring in order to prevent clumping. The dissolver bladewas rotated at 1000 rpm until a clear solution could be obtained. In a 4L Diosna granulator bowl, the batch amounts of microcrystallinecellulose, CaboSil (fumed silica) and croscarmellose sodium were mixedfor 2 minutes in the high shear granulator using the impeller under adry state so as to get a uniform mixture. A peristaltic pump was set upto dispense the compound of formula I and granulating fluid at acontrolled rate. A speed of 12 gram/minute provided a steady stream forthe granulating solution containing compound of formula I being addedinto the bed while the impeller speed of the granulator was maintainedat 150-rpm. After addition of the granulating fluid and the rinsesolution making up a total of about 35% w/w ethanol-water with respectto the batch size, a clear growth in particle size was observed and alsotracked by an increase in power consumption by the machine. Thisindicated an end-point of the granulation process. Finally, awet-massing step was carried out at the impeller speed of 250 rpm and achopper speed of 500-rpm in order to produce a uniform granulation. Thegranules were dried in fluid-bed drying equipment at 50° C. inlet airand 35 cubic feet per minute air swaps. The granules dried to moisturecontent of less than 3% w/w when the product temperature equilibrated at42° C. The dried granules were then sized through a miller(Quadro-Comill) to obtain the desired particle size using a #16 meshscreen, a #18 screen and a #20 screen to identify the optimal screensize. These milled granules were mixed with the extra-granular portionof croscarmellose sodium and then lubricated with steric acid. Tabletshaving 100-mg and 300-mg strengths of compound of formula I werecompressed on a Piccola tablet press using a 10-mm diameter roundtooling for the 100-mg strength. The dissolution profiles in the figurebelow suggested that the milling screen size did not affect thedissolution behavior and either screen could be utilized.

EXAMPLE 5

Scale-up of Tablet Formulation up to 3-kg Using an Atomized SprayProcess for Granulation Amount Amount Amount (mg)/ (mg)/ (gm)/ 300-mg100-mg 3000 gm Ingredient tablet tablet batch(S)-2-(4-chlorophenyl)-1-(4- 330 110 997.245R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one monohydrochloridePolyvinyl pyrolidone (PVP K30) 25 8.33 75.0 Butylated hydroxyl anisole 10.33 3.0 Croscarmellose sodium (internal 25 10 75.0 phase)Croscarmellose sodium (external 25 6.67 75.0 phase) Fumed silica(Aerosil 200) 150 50.0 450.0 Microcrystalline cellulose (PH 101) 435.8145.3 1307.3 *Ethanol/Water q.s. q.s. q.s. Stearic acid 12.5 4.20 37.5*Ethanol/water is evaporated during drying

The formulation shown above was processed in a VG-25 L Glatt granulatorbowl. PVP-K-30 (75 g) and BHA (3 g) were dissolved into a mixture of 489mL ethanol (200 proof) and 489 mL water.(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I) was slowly added to the vesselcontaining the BHA and PVP solution in ethanol-water. The compound offormula I was dissolved under high speed stirring with a dissolver bladein order to prevent clumping. The dissolver blade was rotated at 1000rpm until a clear solution could be obtained. In a VG-25 L Glattgranulator bowl, the batch amounts of microcrystalline cellulose,Aerosil 200 (fumed silica) and croscarmellose sodium were mixed for 2minutes in the high shear granulator using the impeller under a drystate so as to get a uniform mixture. A peristaltic pump was set up todispense the compound of formula I and granulating fluid at a controlledrate and the solution was sprayed on to the powder bed of cellulose andsilica using an atomization nozzle (Spray Systems) with a atomizingpressure of 3 psi. A speed of 91 gram/minute provided a good spraypattern for distributing the granulating solution containing compound offormula I over the powder bed while the impeller speed of the granulatorwas maintained at 100-rpm. After addition of the granulating fluid andthe rinse solution (about 207 grams) making up a total of about 41% w/wethanol-water with respect to the batch size, a clear growth in particlesize was observed and also tracked by an increase in power consumptionby the machine. This indicated an end-point of the granulation process.Finally, a wet-massing step was carried out at the impeller speed of 140rpm and a chopper speed of 500-rpm in order to produce a uniformgranulation. The granules were dried in fluid-bed drying equipment at50° C. inlet air and 65 cubic feet per minute air swaps. The granulesdried in a fluid-bed dryer to moisture content of less than 3% w/w whenthe product temperature equilibrated at 42° C. The dried granules werethen sized through a miller (Fitz-mill with knives forward) to obtainthe desired particle size using a #16 mesh screen, a #18 screen and a#20 screen to identify the optimal screen size. These milled granuleswere mixed with the extra-granular portion of croscarmellose sodium andthen lubricated with steric acid. Tablets having 100-mg and 300-mgstrengths of compound of formula I were compressed on a Piccola tabletpress using a 10-mm diameter round tooling for the 100-mg strength andplain capsule shaped tooling having the dimensions of 0.3437″×0.7500″capsule for the 300-mg strength tablets.

FIG. 24 shows that the(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride is entrapped in an amorphous form in the formulation.

EXAMPLE 6

Tablet Formulation Using a Direct Wet Granulation Approach to Producethe Amorphous Form of (S)-2-(4-chlorophenyl)-1-(44(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino) propan-1-one monohydrochloride AmountAmount Amount (mg)/ (mg)/ (gm)/ 300-mg 100-mg 150 gm Ingredient tablettablet batch (S)-2-(4-chlorophenyl)-1-(4- 325.7 108.6 48.945R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3 - (isopropylamino)propan-1-one monohydrochloridePolyvinyl pyrolidone (PVP K30) 25 8.33 1.25 Butylated hydroxyl anisole 10.33 0.15 Croscarmellose sodium (internal 25 8.33 3.75 phase)Croscarmellose sodium (external 25 8.33 3.75 phase) Fumed Silica(Cabosil M5P) 150 50.0 22.50 Microcrystalline cellulose (PH 101) 435.8145.3 65.4 *Ethanol/Water q.s. q.s. q.s. Stearic acid 12.5 4.2 1.9*Ethanol/water is evaporated during drying

BHA and PVP were dissolved into the ethanol-water solution (50:50 mix tomake a total of 30 grams). In a 1.0 L Diosna granulator bowl, the batchamounts of(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I), microcrystalline cellulose,Cabosil M5P and croscarmellose sodium were mixed for 2 minutes in thehigh shear granulator using the impeller under a dry state so as to geta uniform mixture. This was followed by drop-wise addition of thesolution containing the BHA and PVP dissolved in ethanol and water,under constant agitation of the powder bed in the high shear granulator.After adding all the solution, the beaker was rinsed with about 30 gramsof ethanol/water and added drop wise into the granulation underagitation to so as to ensure the entire batch amount of solution isincorporated into the granulation. This was followed by a final rinsestep of about 20 grams ethanol/water also added with agitation. Aftercompletion of the rinse addition, the impeller speed was increased andthe chopper blade was turned on so as to perform the kneading or wetmassing and facilitate particle growth. After about 2 minutes ofkneading, a clear visual increase in particle size was observable andthe granulation end-point could be confirmed by granule squeeze test.The granules were dried in a tray oven for about 4.5 hours to remove theethanol and water. The final loss on drying from the granules wasmeasured to be less than 3% w/w suggesting a dry granulation. Using thedried granules and re-calculating the exact amount of croscarmellosesodium and stearic acid required for the batch, pre-screened stearicacid was added stepwise to the batch and mixed on a turbula mixer. Thefinal lubricated granulation was compressed on a Carver hydraulic pressusing capsule shaped tooling in order to compress 300-mg potency tabletsat a press weight of 1000-mg. The powder X-ray diffractograms for thegranulation suggests that the compound(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I) is converted to an amorphousstate with this granulation method due to the exposure to an aqueousenvironment during granulation and removal of the ethanol waterapparently and unexpectedly removes and residual crystalline orderpresent in the material.

EXAMPLE 7

Scale-up of Tablet Formulation Using a Direct Wet Granulation Approachto Produce the Amorphous Form of (S)-2-(4-chlorophenyl)-1-(4-45R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[cipyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-onemonohydrochloride Amount Amount Amount (mg)/ (mg)/ (gm)/ 300-mg 100-mg600 gm Ingredient tablet tablet batch (S)-2-(4-chlorophenyl)-1-(4- 325.7108.6 195.4 45R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride Polyvinyl pyrolidone (PVPK30) 25 8.33 15.0 Butylated hydroxyl anisole 1 0.33 0.60 Croscarmellosesodium (internal 25 8.33 15.0 phase) Croscarmellose sodium (external 258.33 15.0 phase) Fumed Silica (Cabosil M5P) 150 50.0 90.0Microcrystalline cellulose (PH 101) 435.8 145.3 261.5 *Ethanol/Waterq.s. q.s. q.s. Stearic acid 12.5 4.2 7.5 *Ethanol/water is evaporatedduring drying

BHA and PVP were dissolved into the ethanol-water solution (50:50 mix tomake a total of 300 grams). In a 4.0 L Diosna granulator bowl, the batchamounts of(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I), microcrystalline cellulose,Cabosil M5P and croscarmellose sodium were mixed for 2 minutes in thehigh shear granulator using the impeller under a dry state so as to geta uniform mixture. This was followed by addition of the solution using aperistaltic pump at a pum rate of 20 grams per minute to obtain a steadystream of granulating fluid containing the BHA and PVP dissolved inethanol and water, under constant agitation of the powder bed in thehigh shear granulator at 170 rpm. After adding all the solution, thebeaker was rinsed with about 30 grams of ethanol/water and added dropwise into the granulation under agitation to so as to ensure the entirebatch amount of solution is incorporated into the granulation. Aftercompletion of the rinse addition, the impeller speed was increased to200 rpm and the chopper blade was turned on so as to perform thekneading or wet massing and facilitate particle growth. After about 2minutes of kneading, a clear visual increase in particle size wasobservable and the granulation end-point could be confirmed by granulesqueeze test. The granules dried in a fluid-bed dryer to moisturecontent of less than 3% w/w when the product temperature equilibrated at42° C. The dried granules were then sized through a miller (Fitz-millwith knives forward) to obtain the desired particle size using a #16mesh screen, a #18 screen and a #20 screen to identify the optimalscreen size. These milled granules were mixed with the extra-granularportion of croscarmellose sodium and then lubricated with steric acid.Tablets having 100-mg and 300-mg strengths of compound of formula I werecompressed on a Piccola tablet press using a 10-mm diameter roundtooling for the 100-mg strength and plain capsule shaped tooling havingthe dimensions of 0.3437″×0.7500″ capsule for the 300-mg strengthtablets.

FIG. 25 shows that the(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride is entrapped in an amorphous form in the formulationeven after scaling up the process by a magnitude of 5×.

EXAMPLE 8

Tablet Formulation Using a Direct Wet Granulation Approach to Producethe Amorphous Form of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride in a 400-mg tabletAmount Amount Amount (mg)/ (mg)/ (gm)/ 400-mg 100-mg 150 gm Ingredienttablet tablet batch (S)-2-(4-chlorophenyl)-1-(4- 434.3 144.8 65.2((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one monohydrochloridePolyvinyl pyrolidone (PVP K30) 25 8.33 3.75 Butylated hydroxyl anisole 10.33 0.15 Croscarmellose sodium (internal 25 8.33 3.75 phase)Croscarmellose sodium (external 25 8.33 3.75 phase) Fumed Silica(Cabosil M5P) 150 50.0 22.50 Microcrystalline cellulose (PH 101) 327.2109.1 49.1 *Ethanol/Water q.s. q.s. q.s. Stearic acid 12.5 4.2 1.9*Ethanol/water is evaporated during drying

BHA and PVP were dissolved into the ethanol-water solution (50:50 mix tomake a total of 30 grams). In a 1.0 L Diosna granulator bowl, the batchamounts of(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride (compound of formula I), microcrystalline cellulose,Cabosil M5P and croscarmellose sodium were mixed for 2 minutes in thehigh shear granulator using the impeller under a dry state so as to geta uniform mixture. This was followed by drop-wise addition of thesolution containing the BHA and PVP dissolved in ethanol and water,under constant agitation of the powder bed in the high shear granulatorat 150 rpm. After adding all the solution, the beaker was rinsed withabout 30 grams of ethanol/water and added drop wise into the granulationunder agitation to so as to ensure the entire batch amount of solutionis incorporated into the granulation. This was followed by a final rinsestep of about 30 grams ethanol/water also added with agitation. Aftercompletion of the rinse addition, the impeller speed was increased andthe chopper blade was turned on so as to perform the kneading or wetmassing and facilitate particle growth. After about 2 minutes ofkneading, a clear visual increase in particle size was observable andthe granulation end-point could be confirmed by granule squeeze test.The granules were dried in a tray oven for about 4.5 hours to remove theethanol and water. The final loss on drying from the granules wasmeasured to be less than 3% w/w suggesting a dry granulation. Using thedried granules and re-calculating the exact amount of croscarmellosesodium and stearic acid required for the batch, pre-screened stearicacid was added stepwise to the batch and mixed on a turbula mixer. Thefinal lubricated granulation was compressed on a Carver hydraulic pressusing capsule shaped tooling in order to compress 400-mg potency tabletsat a press weight of 1000-mg.

EXAMPLE 9(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride Capryolate and Lauryl glycolate solvate

Capryolate Solvate

(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride was dissolved 47.5% w/w in 52.5% w/w Capryol 90 withrepeated sonication (sonicating bath and overhead sonicator), stirringand heating at 60-70° C. A clear solution was obtained which produced awhite precipitate in 2 months upon standing at room temperature. Theprecipitate was characterized as capryol solvate.

Table 2 below shows the characteristic XRPD peaks of the crystallinesolvate.

TABLE 2 2-Theta d(Å) BG Height H% Area A% FWHM  6.517 13.5521 604 31644100.0 154231 100.0 0.069  6.934 12.7368 566 15942  50.4  76663  49.70.068 10.692  8.2674 531  8042  25.4  42607  27.6 0.075 12.282  7.2005588  2507  7.9  14932  9.7 0.085 13.839  6.3936 509  2993  9.5  18931 12.3 0.090 15.607  5.6734 622  5271  16.7  30892  20.0 0.083 18.465 4.8012 622 19212  60.7 135634  87.9 0.100 18.918  4.6871 622  5360 16.9  65512  42.5 0.174 19.520  4.5440 957  2727  8.6  17618  11.40.092 21.409  4.1472 969 11517  36.4  89885  58.3 0.111Lauryl Glycol Solvate

(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride was dissolved 47.5% w/w in 52.5% w/w lauryl glycolwith repeated sonication (sonicating bath and overhead sonicator),stirring and heating at 60-70° C. A clear solution was obtained whichproduced a white precipitate was obtained upon storage in 4 weeks at 25°C./60% RH. The precipitate was characterized as laurylglycolate solvate.

Table 3 below shows the characteristic XRPD peaks of the crystallinesolvate.

TABLE 3 2-Theta d(Å) BG Height H% Area A% FWHM  6.515 13.5569  598 36382100.0 259720 100.0 0.101  6.947 12.7146  596 20068  55.2  97362  37.50.069 10.677  8.2793  567  4232  11.6  25836  9.9 0.087 13.840  6.3936 547  4033  11.1  31256  12.0 0.110 15.592  5.6785  595  6471  17.8 45117  17.4 0.099 18.465  4.8011  662 10757  29.6 109728  42.2 0.14518.918  4.6873  662  9863  27.1 103366  39.8 0.149 19.521  4.5438 1090 3760  10.3  31463  12.1 0.119 21.058  4.2155  974  3663  10.1  55103 21.2 0.214 21.376  4.1534  996  6914  19.0  79912  30.8 0.164 23.598 3.7672  963  2793  7.7  58900  22.7 0.300

Variable temperature XRD showed that both solvates are stable up to 80°C. At temperatures≧80° C., there is substantial loss of crystallinity.In both samples, they appear to be X-ray amorphous at 90° C. and above(due to melting of the lattice solvent and dissolution of the solidphase in it as confirmed by hot stage microscopy). Taken together, theanalysis of the solvates shows them to be highly crystalline, stable,non-hygroscopic, have about 18-22% solvent uptake in the crystal latticeand at ambient temperature, exhibit almost 2 fold lower solubility inrespective solvents than the material of Example 1.

EXAMPLE 10 Amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride

The material of Example 1 was dissolved in 10 volumes of ethanol. A stirbar was added to the rotovap flask and the solvent was evaporated underreduced pressure on a rotary evaporator to give foam. The foam isscraped to knock down the foam and drying is continued until a freeflowing solid is obtained. A sample of the product (4.70 mg), is placedin a pre-weighed aluminum pan and placed in the oven on a TA InstrumentsQ5000SA vapor sorption analyzer. The sample was heated to 50° C. under astream of dry nitrogen and equilibrated. The relative humidity wasincreased to 50% at 50° C. and held there for 2 hours. The humidity wasthen lowered to 0% RH while the temperature was maintained at 50° C. andheld there for 2 hours. The sample was then analyzed by XRPD (FIG. 27)and modulated DSC (FIG. 28). The DVS program is graphically shown inFIG. 26. The DSC method was done by using modulated DSC at a rate of 2°C./minute with modulation of ±1° C. every 60 seconds using a lightlycrimped pan which allows solvent to escape during the run.

EXAMPLE 11(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride toluene solvate

Toluene, 5 mL, was added to material from Example 1 (20 mg). The slurrywas heated to 50° C. in a shaker block for 1 day. Most of the solid wasdissolved and then a small amount precipitated from solution at 50° C.Most of the liquid was removed and the suspension was allowed to cool toroom temperature. Crystals suitable for structure determination wereobtained. The crystals obtained contained 0.64 moles of toluene/mole ofthe compound of Formula I.

A single crystal was obtained with the following data: formulaC55H74C14N10O4, formula weight 1081.04, space group P 21 21 21 (No. 19),a, Å 14.074(2), b, Å 16.621(2), c, Å 24.363(3), α, deg 90, β, deg 90, γ,deg 90, V, Å³ 5699.0(14), Z 4, d_(calc), g cm⁻³ 1.260, temperature, K100. radiation (wavelength, Å) Cu K_(α) (1.54184), diffractometer BrukerAPEX-II CCD′, h, k, l range −16 to 16 −19 to 20 −29 to 29, θ range, deg3.29-68.397, programs used SHELXTL 2013, data collected 10425, uniquedata 9646, R(F_(o)) 0.076, R_(w)(F_(o) ²) 0.2010, goodness of fit 1.41,and is shown in FIG. 29.

Amorphous compound of Formula I was dissolved in a mixture of toluene, 1mL, and tetrahydrofuran, 600 μL. The solution was placed into adesiccator to slowly evaporate. The lid of the desiccator was openedperiodically to allow the solvent vapors to escape. After 7 days,crystals were isolated from the remaining solution (FIG. 30A). Theproduct was dried at 50° C. and 50 torr for 1 hour to give a partiallydesolvated toluene solvate. The XRPD of the solvate and partiallydesolvated solvate are shown in FIGS. 30A and 30B, respectively.

EXAMPLES 12 A-C Amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride prepared by spray-drying

Amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride was prepared by spray drying solutions of variousforms of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride. The conditions and results of several experiments areshown below in Table 4 (See FIGS. 31A for 12A, 31B for 12B and 31C for12C).

TABLE 4 Example Number 12A 12B 12C Loop Open Open Open Feed compositionStarting material Compound Compound Compound of Formula I of of FormulaI Ethyl Formula I Ethyl Acetate (Example 1) Acetate Solvate SolvateProcess Solvent Ethanol Ethanol Water Feed properties Total StartingMaterial^(a)) g 50.0 50.0 25.0 Total Process Solvent^(a)) g 250.0 250.0100.0 Feed solution g 300.0 300.0 125.0 C_feed % w/w 16.7 16.7 20.0Spray drying parameters T_in ° C. 120 ± 1 119 ± 1 154 ± 1 T_out ° C.  69± 1  69 ± 1  90 ± 1 F_feed mL/min 15 15 5 Rotamer level mm 40 40 40Drying time min 23 23 23 Process yield Yield g 28.8 48.4 15.0 Yield % 5897 60 Analytical results Water content % w/w 0.89 0.43 1.02 Ethanol %w/w 2.19 2.78 0.01 Ethyl acetate % w/w 0.25 0.01 0.23 ^(a))Nocorrections were made to consider the amount of solvent in the crystal

EXAMPLE 11(5)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride ethyl acetate solvate

In a visually clean 10 L jacketed cylindrical vessel under nitrogen wascharged GDC-0068•HCl (500 g) and ethyl acetate (5 L). The resultingslurry was heated to 60° C. for 72 hours and aliquots were pulled tomonitor the conversion to EtOAc solvate by XRPD analysis. The slurry wascooled to 5° C., filtered and dried under vacuum at room temperature for5 min.

Alternative Procedure

A saturated solution of material from Example 1 was prepared byslurrying material from Example 1 in ethyl acetate at 50° C. overnightand then filtering through a hot, 50° C., syringe filter fitted with a0.45 μm filter while the slurry was still hot. The resulting solutionwas allowed to slowly cool to room temperature in a sealed vial andallowed to stand for 2 weeks. Crystals of suitable quality for structuredetermination were formed (See FIG. 34). and the data is shown in Table5 below.

TABLE 5 formula C₂₈H₄₁Cl₂N₅O₄ formula weight 582.58 space group P 21 2121 (No. 19) a, Å 16.5805 (3)  b, Å 17.6134 (3)  c, Å 20.7419 (15) V, Å³6057.4 (5) Z 8 d_(calc), g cm⁻³ 1.278 temperature, K 150 radiation(wavelength, Å) Cu K_(α) (1.54184) diffractometer Rigaku RAPID-II h, k,l range −17 to 19 −11 to 20 −17 to 24 Θ range, deg 4.26-133.19 programsused SHELXTL 2008 data collected 10507 R(F_(o)) 0.053 R_(w)(F_(o) ²)0.108 goodness of fit 1.115 absolute structure Flack parameterdetermination (0.00(2))

Additional solvates: Chlorobenzene solvate: Chlorobenzene, approximately2 mL, was added to material from Example 1, 66 mg. The slurry was heatedto 50 C in a shaker block for 1 day. The solid dissolved. The solutionwas cooled to room temperature, placed in a freezer at approximately −18C and allowed to stand for 24 days. Solid appeared. The solution wasdecanted while still cold to remove most of the solvent to give crystalsof the chlorobenzene solvate.

Ethylbenzene solvate: Ethyl benzene, 5 mL, was added to material fromexample 1, 29 mg. The slurry was heated to 50 C on a shaking block for 2days. The slurry was allowed to cool to room temperature and allowed tostand for 1 week to give the ethylbenzene solvate of compound of formulaI. Solids were collected by filtration and analyzed while wet withsolvent.

ortho-Xylene solvate: ortho-Xylene, 4 mL, was added to material fromexample 1, 66 mg. The slurry was heated to 50 C for 2 days and thencooled to room temperature and allowed to stand for 6 days at roomtemperature. Solid was pulled from the slurry and analyzed withoutdrying. The suspension was allowed to stand for about 1 month. A secondsample was collected by filtering the suspension and analyzing the solidwas still damp with solvent to give the ortho-xylene solvate of compoundof formula I.

meta-Xylene solvate: meta-Xylene, 3 mL, was added to material fromexample 1, 64 mg. The slurry was heated to 50 C for 2 days and thencooled to room temperature and allowed to stand for 12 days at roomtemperature. A sample was collected by filtering the suspension andanalyzing the solid was still damp with solvent to give the meta-xylenesolvate of compound of formula I. meta-Xylene, 5 mL, was added tomaterial from example 1, 24 mg. The slurry was heated to 50 C for 2 daysand then cooled to room temperature and allowed to stand for 15 days atroom temperature. A sample was collected by filtering the suspension andanalyzing the solid was still damp with solvent to give the meta-xylenesolvate of compound of formula I.

para-Xylene solvate: para-Xylene, 4 mL, was added to material fromexample 1, 81 mg. The slurry was heated to 50 C for 2 days and thencooled to room temperature and allowed to stand for 6 days at roomtemperature. A sample was collected by filtering the suspension andanalyzing the solid was still damp with solvent to give the para-xylenesolvate of compound of formula I.

Cumene solvate: Cumene, 2 mL, was added to material from example 1, 64mg. The slurry was heated to 50 C for 2 days and then cooled to roomtemperature and allowed to stand for 11 days at room temperature. Asample was collected by filtering the suspension and analyzing the solidwas still damp with solvent to give the cumene solvate of compound offormula I.

Tetralin solvate: Tetralin, 3 mL, was added to material from example 1,64 mg. The slurry was heated to 50 C for 2 days and then cooled to roomtemperature and allowed to stand for 12 days at room temperature. Asample was collected by removing solid with a spatula from thesuspension and analyzing the solid was still wet with solvent to givethe tetralin solvate of compound of formula I.

Methyl ethyl ketone solvate: Methyl ethyl ketone (1 mL) was added to theamorphous material (222.7 mg). The material was sonicated at 28° C. for5 minutes. The solid almost dissolved after 2 minutes. The sample wasremoved from the sonication bath and became cloudy prior to becoming amass of solid with no visible solvent present. Methyl ethyl ketone (100μL) was added to the amorphous material (22.2 mg). The solid dissolved.Heptane (100 μL) was added along with a seed of amorphous material. Thematerial was slurried for 4 days and the solid isolated while still dampwith solvent to give the MEK solvate.

Methyl isobutyl ketone solvate: Methyl isobutyl ketone, 1 mL, was addedto solid from example 1, 32.3 mg. The slurry was heated to 50 C for 2days on a shaking block and then allowed to stand at room temperaturefor 15 days. Sample was collected by filtering the suspension andanalyzing the solid while the solid was still damp with solvent to givethe methyl isobutyl ketone solvate of compound of formula I.

Methyl Butyl ketone solvate: Methyl butyl ketone, 3 mL, was added tomaterial from example 1, 63 mg. The solid dissolved. The solution wasplaced in a freezer at approximately −18 C and allowed to stand for 25days. Solid appeared. The solution was decanted while still cold toremove most of the solvent to give crystals of the methyl butyl ketonesolvate. The solid was initially analyzed by removing a solid aliquotfrom the suspension with a spatula. The solid was reanalyzed bycollecting solid via filtration and analyzing the solid while still dampwith solvent.

Diisobutyl ketone: A solution of diisobutyl ketone and isopropanol(90:10 v:v ratio) was added to the HCl salt at a concentration of 50 mgHCl salt to solvent. The solids dissolved and more HCl salt was added togive a slurry. A pasty solid was isolated after were stirred at roomtemperature. The material was dried at 50° C. under vacuum (50-100 torr)to give the diisobutyl ketone solvate.

Chloroform solvate hydrate: The HCl salt (2.63 mg) was treated with amixture of heptane (2 mL) and chloroform (0.5 mL). The slurry was heatedat 60° C. A cluster of solids, needles, were observed in the vial. Thevial was allowed to stand for 23 days where most of the solvent hadevaporated. A large plate was observed in the vial that was suitable forsingle crystal structure determination. The chloroform solvate hydratewas found to be partially desolvated and contained about 1 mole ofchloroform and 0.25 mole of water per API molecule

Methyl acetate solvate: Methyl acetate, 4 mL, was added to material fromexample 1, 24 mg. The solid dissolved. The solution was filtered into a4 mL vial and the cap removed. The vial was placed inside a 20 mLscintillation vial containing heptane and the lid placed on the 20 mLvial. The vials were not disturbed. The solvents were allowed to diffuseinto one another. Crystals suitable for structure determination wereobtained. The crystal obtained contained 0.71 moles of methylacetate/mole of compound of formula I and the solvent was disordered.Methyl acetate solvate: Methyl acetate, 2.5 mL, was added to solid fromexample 1, 111 mg. The slurry was heated to 50 C overnight on a shakingblock and then allowed to stand at room temperature for 1 week. A samplewas collected by filtering the suspension and analyzing the solid whilethe solid was still damp with solvent to give the methyl acetate solvateof compound of formula I.

Propyl acetate solvate: Propyl acetate, 6 mL, was added to material fromexample 1, 31 mg. The suspension was heated at 50° C. in a shaker blockand then allowed to cool to room temperature. Crystals suitable forstructure determination were obtained. Propyl acetate, 2 mL, was addedto material from example 1. The slurry was heated to 50° C. overnightand allowed to stand for 1 week. Solid was collected by vacuumfiltration and the solid collected while still damp with liquid to givethe propyl acetate solvate.

Isopropyl acetate solvate: Isopropyl acetate, 1 mL, was added tomaterial from example 1, 55 mg. The slurry was heated to 50 C for 2 daysand then cooled to room temperature and allowed to stand for 15 days atroom temperature. A sample was collected by filtering the suspension andanalyzing the solid was still damp with solvent to give the isopropylacetate of compound of formula I.

Isobutyl acetate solvate: Isobutyl acetate, 2 mL, was added to solidfrom example 1, 68 mg. The slurry was heated to 50 C for 2 days on ashaking block and then allowed to stand at room temperature for 2 weeks.Sample was collected by filtering the suspension and analyzing the solidwhile the solid was still damp with solvent to give the methyl isobutylketone solvate of compound of formula I.

Tert-butyl acetate solvate: Tert-butyl acetate, 2 mL, was added to solidfrom example 1, 63 mg. The slurry was heated to 50 C for 2 days on ashaking block and then allowed to stand at room temperature for 2 weeks.Sample was collected by filtering the suspension and analyzing the solidwhile the solid was still damp with solvent to give the methyl isobutylketone solvate of compound of formula I.

Ethyl ether solvate: (69659-50) Material from example 1 was dissolved inethanol and the solvent removed under reduced pressure on a rotaryevaporator to give amorphous material. The solid was slurried for 22days at room temperature. Sample was collected by filtering thesuspension and analyzing the solid while the solid was still damp withsolvent to give the ethyl ether solvate of compound of formula I.

Amyl acetate solvate: A solution of amyl acetate and isopropanol (95:5v:v ratio) was added to the HCl salt contained in a 1 mL vial at aconcentration of 60 mg HCl salt to solvent. The material was heated to100° X at a rate of 0.3° C./minute and then cooled to room temperatureat the same rate. The visal contents were stirred at room temperatureover the weekend. The solid was collected by filtration and dried at 50°C. under vacuum (50-100 torr).

Glycerol triacetate solvate: Triacetyl glycerol (0.2 mL) was added tosolid from example 1, 19.5 mg. The slurry was mixed on a shaking blockat 25° C. for 2 months. The solid was isolated by centrifugation on anultra centrifuge at 1400 rpm using a 0.45 μm pore filter to give a whitesolid that was identified as the glycerol triacetate solvate.

Ethyl ether-ethanol-hydrate: Material from example 1 was dissolved inethanol and the solvent removed under reduced pressure on a rotaryevaporator to give amorphous material. The solid was dissolved indichloromethane using a 4 mL vial and was placed inside a larger vial,20 mL, containing diethyl ether. The small vial cap was removed and acap placed on the larger vial. The solvents were allowed to diffuse intoone another by vapor diffusion. Large crystals were obtained that weresuitable for structure determination. The structure was solved and foundto be the diethyl ether-ethanol-hydrate of compound of formula I.

Tert-Butyl methyl ether solvate: Tert-Butyl methyl ether, 5 mL, wasadded to solid from example 1, 26 mg. The slurry was heated to 50 C for2 days on a shaking block and then allowed to stand at room temperaturefor 15 days. Sample was collected by filtering the suspension andanalyzing the solid while the solid was still damp with solvent to givethe tert-butyl methyl ether solvate of compound of formula I.

1,2-dimethoxyethane solvate: 1,2-Dimethoxyethane, 0.5 mL, was added tosolid from example 1, 27 mg. The solid dissolved. The solution wasfiltered into a 4 mL vial and the cap removed. The vial was placedinside a 20 mL scintillation vial containing octane and the lid placedon the 20 mL vial. The vials were not disturbed. The solvents wereallowed to diffuse into one another. Crystals suitable for structuredetermination were obtained. The crystal obtained contained 0.32 molesof 1,2-dimethoxyethane/mole of compound of formula I.

1,2-diethoxyethane solvate: 1,2-diethoxyethane, 5 mL, was added to solidfrom example 1, 21.9 mg. The slurry was heated to 50 C for 2 days on ashaking block and then allowed to stand at room temperature for 8 days.Sample was collected by filtering the suspension and analyzing the solidwhile the solid was still damp with solvent to give the1,2-diethoxyethane of compound of formula I.

2,2-dimethoxypropane solvate: 2,2-dimethoxypropane, 5 mL, was added tosolid from example 1, 30.5 mg. The slurry was heated to 50 C for 2 dayson a shaking block and then allowed to stand at room temperature for 8days. Sample was collected by filtering the suspension and analyzing thesolid while the solid was still damp with solvent to give the2,2-dimethoxypropane solvate of compound of formula I.

2-methyltetrahydrofuran solvate: 2-methyltetrahydrofuran, 3 mL, wasadded to solid from example 1, 92.2 mg. The slurry was heated to 50 Cfor 2 days on a shaking block and then allowed to stand at roomtemperature for 15 days. Sample was collected by filtering thesuspension and analyzing the solid while the solid was still damp withsolvent to give the 2-methyltetrahydrofuran solvate of compound offormula I.

The amounts of solvent present in solvates of a compound of formula Iwas analysed and is given below in Table 6.

TABLE 6 Single Actual 1 molar crystal Single moles Weight equiv solventcrystal solvent percent solvent amount calculated experi- experi-Solvent % solvent moles weight % mental mental Toluene 15.7 0.64 10.70.24 4.3 Chloroben- 18.5 — — zene Ethylben- 17.7 — — 0.47 9.2% zeneo-xylene 17.7 — — m-xylene 17.7 0.32 6.4 p-xylene 17.7 0.42 8.3 cumene19.5 0.34 7.6 tetralin 21.1 MEK 12.7 MIBK 16.8 0.14 2.8 0.35 6.6 ½ molar9.2% MBK 16.8 0.54 9.9 ½ molar 9.2% DIBK 22.3 0.38 9.9 ½ molar equiv12.6 Chloroform 1.5 molar 1 + ¼ equivalents water MeOAc 13.0 0.71 9.60.5 7.0 PrOAc 17.1 0.33 6.4 iBuOAc 19.0 0.36 7.8 tBuOAc 19.0 0.39 8.4AmylOAc 20.8 0.41 9.7-9.8 glycerol 30.6 0.26 10.3 triacetate 0.5 molaeequiv 18.08 TBME 15.1 DME 15.4 0.32 5.5 DEE 19.3 0.37 7.3 DMP 17.4 0.377.3 MeTHF 14.8 0.43 6.9

ADDITIONAL EMBODIMENTS Embodiment 1

A pharmaceutical formulation comprising amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.

Embodiment 2

The formulation of embodiment 1, further comprising antioxidant.

Embodiment 3

The formulation of embodiment 2, wherein the antioxidant is BHA or BHT.

Embodiment 4

The formulation of embodiment 1, wherein the formulation is liquid fillcapsule for oral delivery.

Embodiment 5

The formulation of embodiment 4, further comprising a liquid fillsolvent selected from propylene glycol monocaprylate, PEG-32 glyceryllaurate, PEG-6 glyceryl oleate, PEG-6 glyceryl linoleate, Propyleneglycol monolaurate, Poloxamer 188, Poloxamer 407, Polyethyleneglycol1500, Propylene glycol, Glycerol (Glycerin), d-alpha tocopheryl PEG-1000succinate and PEG-8 caprylic/capric glycerides.

Embodiment 6

The formulation of embodiment 5, comprising 100 to 400 mg of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.

Embodiment 7

The formulation of embodiment 1, comprising(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, liquid fill solvent selected from capryol 90 andlauroglycol 90 and antioxidant selected from BHT or BHA.

Embodiment 8

The formulation of embodiment 1, wherein the formulation is a tablet fororal delivery.

Embodiment 9

The formulation of embodiment 8, further comprising polyvinylpyrolidone.

Embodiment 10

The formulation of embodiment 9, further comprising anhydrous silicondioxide (precipitated silica/fumed silica/amorphous silica) andmicrocrystalline cellulose.

Embodiment 11

The formulation of embodiment 9, further comprising colloidal silicondioxide (fumed silica) and microcrystalline cellulose.

Embodiment 12

The formulation of embodiment 10, further comprising antioxidantselected from BHA and BHT or Propyl gallate.

Embodiment 13

The formulation of embodiment 11, comprising 100 to 400 mg of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.

Embodiment 14

The formulation of embodiment 1, comprising amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, Polyvinyl pyrolidone, Butylated hydroxyl anisole,Croscarmellose sodium, Fumed silica, Microcrystalline cellulose andStearic acid.

Embodiment 15

A crystalline(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride propylene glycol monocaprylate solvate.

Embodiment 16

A crystalline(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride propylene glycol monolaurate solvate.

What is claimed is:
 1. Amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 2. A pharmaceutical formulation comprising amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 3. The formulation of claim 2, further comprisingprecipitated silica, fumed silica or amorphous silica.
 4. Theformulation of claim 3, further comprising microcrystalline cellulose.5. The formulation of claim 4, further comprising antioxidant selectedfrom BHA, BHT or propyl gallate.
 6. The formulation of claim 5, furthercomprising polyvinylpyrrolidone.
 7. The formulation of claim 2,comprising about 100 to 400 mg of(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.8. The formulation of claim 2, wherein the formulation is a tablet fororal delivery.
 9. The formulation of claim 2, further comprisingPolyvinyl pyrolidone, Butylated hydroxyl anisole, Croscarmellose sodium,Fumed silica, Microcrystalline cellulose and Stearic acid.
 10. A processof producing amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, comprising spray drying a mixture comprising(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride or a solvate thereof and solvent.
 11. A process ofproducing amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride, comprising contacting a mixture comprising(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride or a solvate thereof with a gas.
 12. The process ofclaim 11, wherein the gas comprises nitrogen and water.
 13. A tablet fororal delivery comprising amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 14. The tablet of claim 13, comprising about 100 mg(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 15. The tablet of claim 13, comprising about 400 mg(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 16. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 1, comprising onset Tg in the range of about124-130° C.
 17. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 16, wherein said onset Tg is stable for atleast about 12 weeks.
 18. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 17, comprising water content between about3.5-4.0%.
 19. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-l-yl)-3-(isopropylamino)propan-l-onemonohydrochloride of claim 1, further comprising water, wherein saidwater content remains between about 3.5-4.5% for at least 12 weeks. 20.The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-l-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 1, wherein the X-ray powder diffractionspectrum lacks diffracted peaks.
 21. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 1, wherein the X-ray powder diffractionspectrum lacks a diffracted peak in 2-Theta (+/−0.2) occurring at 7.1.22. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-l-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 1, wherein the X-ray powder diffractionspectrum lacks one or more diffracted peaks in 2-Theta (+/−0.2)occurring at 7.1, 8.4, 8.8, 10.5, 12.7, 13.7, 13.9, 17.4, 21.1 or 22.3.23. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 1, which shows a glass transition in adifferential scanning calorimetry (DSC) spectrum, wherein the glasstransition is evident in a second heating cycle.
 24. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 23, wherein the glass transition onsettemperature is about 114° C.
 25. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 1, which shows a glass transition in amodulated differential scanning calorimetry (DSC) spectrum.
 26. Theamorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 25, wherein the glass transition onsettemperature is about 124-134° C. and the modulated differential scanningcalorimetry (DSC) has a rate of about 2° C./minute with modulation ofabout ±1° C. every 60 seconds.
 27. Isolated amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim
 1. 28. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 27, comprising onset Tg in the range of about124-130° C.
 29. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 28, wherein said onset Tg is stable for atleast about 12 weeks.
 30. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 27, comprising water content between about3.5-4.0%.
 31. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 27, further comprising water, wherein saidwater content remains between about 3.5-4.5% for at least 12 weeks. 32.The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 27, wherein the X-ray powder diffractionspectrum lacks diffracted peaks.
 33. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-l-onemonohydrochloride of claim 27, wherein the X-ray powder diffractionspectrum lacks a diffracted peak in 2-Theta (+/−0.2) occurring at 7.1.34. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 27, wherein the X-ray powder diffractionspectrum lacks one or more diffracted peaks in 2-Theta (+/−0.2)occurring at 7.1, 8.4, 8.8, 10.5, 12.7, 13.7, 13.9, 17.4, 21.1 or 22.3.35. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-l-onemonohydrochloride of claim 27, which shows a glass transition in adifferential scanning calorimetry (DSC) spectrum, wherein the glasstransition is evident in a second heating cycle.
 36. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 35, wherein the glass transition onsettemperature is about 114° C.
 37. The amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 27, which shows a glass transition in amodulated differential scanning calorimetry (DSC) spectrum.
 38. Theamorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride of claim 37, wherein the glass transition onsettemperature is about 124-134° C. and the modulated differential scanningcalorimetry (DSC) has a rate of about 2° C./minute with modulation ofabout ±1° C. every 60 seconds.
 39. A composition consisting essentiallyof amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 40. The process of claim 10, wherein said solvent iswater or ethanol.
 41. The process of claim 10, wherein said spray driedamorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-l-onemonohydrochloride comprises about 0.01 to about 2.5% residual solvent.42. The process of claim 10, wherein said solvate is an ethyl acetatesolvate, said solvent is water, and said spray dried amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride comprises less than about 1.0% w/w water and about0.25% w/w or less ethyl acetate.
 43. The process of claim 10, furthercomprising drying the spray-dried amorphous(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride.
 44. The process of claim 43, wherein said spray driedamorphous(S)-2-(4-chlorophenyl)-1-(4((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onemonohydrochloride comprises less than about 0.5% solvent after saiddrying.